CN114404366A - Sophora flavescens total alkali percutaneous absorption nano microemulsion - Google Patents
Sophora flavescens total alkali percutaneous absorption nano microemulsion Download PDFInfo
- Publication number
- CN114404366A CN114404366A CN202210147916.4A CN202210147916A CN114404366A CN 114404366 A CN114404366 A CN 114404366A CN 202210147916 A CN202210147916 A CN 202210147916A CN 114404366 A CN114404366 A CN 114404366A
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- China
- Prior art keywords
- geniposide
- transdermal absorption
- solution
- matrine
- absorption nano
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- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 65
- 238000010521 absorption reaction Methods 0.000 title claims abstract description 58
- 241000246044 Sophora flavescens Species 0.000 title description 3
- 239000003513 alkali Substances 0.000 title description 3
- IBFYXTRXDNAPMM-BVTMAQQCSA-N Geniposide Chemical compound O([C@@H]1OC=C([C@@H]2[C@H]1C(=CC2)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBFYXTRXDNAPMM-BVTMAQQCSA-N 0.000 claims abstract description 62
- IBFYXTRXDNAPMM-FZEIBHLUSA-N Geniposide Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]2[C@@H]1CC=C2CO IBFYXTRXDNAPMM-FZEIBHLUSA-N 0.000 claims abstract description 62
- VGLLGNISLBPZNL-RBUKDIBWSA-N arborescoside Natural products O=C(OC)C=1[C@@H]2C([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)=C(CO)CC2 VGLLGNISLBPZNL-RBUKDIBWSA-N 0.000 claims abstract description 62
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims abstract description 32
- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229930014456 matrine Natural products 0.000 claims abstract description 31
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000661 sodium alginate Substances 0.000 claims abstract description 28
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 28
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 28
- 229920000642 polymer Polymers 0.000 claims abstract description 23
- 239000000839 emulsion Substances 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 14
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940071160 cocoate Drugs 0.000 claims abstract description 10
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 claims abstract description 7
- 229920002581 Glucomannan Polymers 0.000 claims abstract description 7
- 229940046240 glucomannan Drugs 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 36
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 26
- 238000009396 hybridization Methods 0.000 claims description 25
- 238000002156 mixing Methods 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000008055 phosphate buffer solution Substances 0.000 claims description 21
- 238000009210 therapy by ultrasound Methods 0.000 claims description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 238000001879 gelation Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 9
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 7
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 7
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 5
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 238000000527 sonication Methods 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 16
- 239000002245 particle Substances 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 14
- 238000003860 storage Methods 0.000 abstract description 6
- 239000013543 active substance Substances 0.000 abstract description 5
- 230000002776 aggregation Effects 0.000 abstract description 5
- 230000007774 longterm Effects 0.000 abstract description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004220 aggregation Methods 0.000 abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 229910000077 silane Inorganic materials 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 32
- 210000003491 skin Anatomy 0.000 description 23
- 239000003814 drug Substances 0.000 description 15
- 210000001772 blood platelet Anatomy 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 206010052428 Wound Diseases 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 238000005452 bending Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000013271 transdermal drug delivery Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010039509 Scab Diseases 0.000 description 3
- 241000219784 Sophora Species 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 241000411851 herbal medicine Species 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241001145009 Sophora alopecuroides Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010408 film Substances 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
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- 239000010410 layer Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XVPBINOPNYFXID-JARXUMMXSA-N 85u4c366qs Chemical compound C([C@@H]1CCC[N@+]2(CCC[C@H]3[C@@H]21)[O-])N1[C@@H]3CCCC1=O XVPBINOPNYFXID-JARXUMMXSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
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- 238000005054 agglomeration Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
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- 229960001631 carbomer Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
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- 239000013043 chemical agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229930182491 iridoid glucoside Natural products 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
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- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/489—Sophora, e.g. necklacepod or mamani
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nanotechnology (AREA)
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- Crystallography & Structural Chemistry (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Manufacturing & Machinery (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- General Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
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- Rheumatology (AREA)
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- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a transdermal absorption nano microemulsion of total matrine, which uses sucrose-cocoate and isopropyl myristate to coat geniposide and form geniposide emulsion; performing hydroformylation treatment on sodium alginate, and performing nucleophilic addition reaction on carbonyl and silane containing amino to prepare a hybrid polymer solution; and cooling and gelling the geniposide emulsion, the total matrine, the glucomannan and the hybrid polymer solution under an acidic condition to prepare the transdermal absorption nano microemulsion of the total matrine. The invention has good transdermal effect and ductility, can be tightly attached to the skin, and is favorable for releasing anti-inflammatory active substances; the drug effect particles in the microemulsion have stable quality in the long-term storage process, do not generate aggregation or disintegration, and have photo-thermal stability; the geniposide can be effectively released from the microemulsion for a long time, and the anti-inflammatory effective time is prolonged.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a matrine transdermal absorption nano microemulsion.
Background
The matrine is a mixture of various alkaloids, is mainly extracted from traditional Chinese herbal medicines such as radix sophorae flavescentis, sophora alopecuroide, sophora subprostratae and the like, can inhibit the growth of various microorganisms and even kill the microorganisms, and can be used as an ideal plant-derived antibacterial agent and an ideal anticancer agent.
Transdermal drug delivery preparations are widely used in the field of pharmaceutical preparations. Compared with other administration modes, the transdermal administration preparation has the following advantages: reduce the burden of the liver and reduce the toxic and side effects. The drug administration interval is prolonged, and the drug can enter the body at a constant rate for a long time by one-time drug administration; avoid the degradation of the medicine by the gastrointestinal tract and improve the curative effect. Can be used for local treatment, and can also reach the whole body through the skin to play the role of whole body treatment. Convenient use, medical resource saving, and administration and termination of administration at any time. Transdermal absorption of a drug refers to the process by which the drug, after acting on the skin, permeates or accumulates at a certain rate in the layers of the skin, producing a local or systemic therapeutic effect. However, there are certain limitations, the environment of transdermal drug delivery is complex, unstable external environments such as temperature and light exist, the specific surface area of the transdermal drug delivery preparation is large, the surface free energy is high, and agglomeration, flocculation and the like easily occur, so the physical and chemical stability of the transdermal drug delivery preparation is always a focus and a hot point of research.
Patent CN106031718A provides a preparation method of matrine transdermal agent, which comprises the following steps: (1) dissolving matrine in anhydrous alcohol and distilled water in sequence; (2) heating to prepare a chitosan glacial acetic acid solution; (3) mixing the Chinese medicinal extract with chitosan oligosaccharide glacial acetic acid solution; (4) adding the mixture into an emulsifying system to emulsify, (5) carrying out a crosslinking reaction on an emulsified product, (6) processing the crosslinking reaction product in a washing, precipitating, centrifuging and drying mode to obtain the transdermal drug membrane loaded with the traditional Chinese medicine extract. However, the patent medicine has poor transdermal effect, low biocompatibility and weak light stability, and medicinal components are easy to lose after long-term storage.
Disclosure of Invention
In view of the above-mentioned defects of the prior art, the technical problems solved by the present invention are: (1) provides the matrine transdermal absorption nano microemulsion which has good transdermal effect and enables the anti-inflammatory active substance to effectively pass through the skin cuticle; (2) the mechanical property and the ductility of the matrine transdermal absorption nano microemulsion are improved, so that the matrine transdermal absorption nano microemulsion can be tightly attached to the skin, and the release of anti-inflammatory active substances is facilitated; (3) the stability of the herbal anti-inflammatory active ingredient geniposide in the microemulsion is improved, the storage time is prolonged, the use condition is expanded, and the drug effect is improved.
The transdermal absorption of geniposide mainly faces several problems, firstly, the combination of the substrate and geniposide has good stability and ductility; the improvement of the stability is beneficial to ensuring the unification of the anti-inflammatory effects of the geniposide under different use environments; the ductility enables the base material to have certain deformation capacity, the base material is more tightly attached to the affected part of the skin, and the geniposide is favorably released and absorbed.
In the prior art, the base material for preparing the microemulsion can be carbomer, chitosan, sodium alginate and hydroxypropyl methyl cellulose generally; the material has good biocompatibility and good water solubility, but the prepared microemulsion generally has the technical problem of poor ductility; in practical use, the transdermal absorption effect of the anti-inflammatory active substance is closely related to the effective contact between the microemulsion and the skin, the base material with poor ductility has the defect that the base material is difficult to be tightly attached along with the change of the skin shape, and especially at the joint movement part, the absorption of the anti-inflammatory component is greatly reduced. Aiming at the technical problem, the inventor uses a hybrid polymer solution and gelatinizes with emulsion coated with anti-inflammatory components to prepare the transdermal absorption nano microemulsion of the total matrine; the matrine transdermal absorption nano microemulsion has a three-dimensional network structure and good ductility, and meanwhile, the structure has the characteristic of porosity and can provide an enough passage for the release of anti-inflammatory components.
A preparation method of a matrine transdermal absorption nano microemulsion comprises the following steps:
s1, mixing 7.5-10 parts of sucrose-cocoate with 7.5-12.5 parts of isopropyl myristate to obtain an oil phase mixture; dissolving 0.16-0.36 part of geniposide in 12-18 parts of water to obtain a geniposide water solution; mixing the oil phase mixture with a geniposide water solution, and performing ultrasonic treatment to obtain a geniposide emulsion;
s2, dissolving 0.25-0.5 part of sodium periodate in 15-30 parts of water to obtain a sodium periodate aqueous solution; adding 4.8-9 parts of sodium alginate and 1.5-3 parts of ethylene glycol into the sodium periodate aqueous solution, and reacting under a light-free condition; filtering the reaction product to obtain filtrate, and freeze-drying to obtain hydroformylation sodium alginate;
s3, dissolving the hydroformylation sodium alginate in 30-50 parts of phosphate buffer solution, and continuously adding 2.2-3.3 parts of gamma-aminopropyltriethoxysilane and 2-3 parts of tetraethoxysilane for hybridization reaction to obtain a hybridization reaction solution;
s4, adding 0.12-0.3 part of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.08-0.15 part of N-hydroxysuccinimide into the hybridization reaction solution, and mixing to obtain a hybridization polymer solution;
s5, mixing the geniposide emulsion obtained in the step S1, 1-3 parts of total matrines, 2-5 parts of glucomannan and the hybrid polymer solution, adjusting the pH value of the solution to 5-5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion of the total matrines. The stratum corneum on the surface layer of the skin provides a natural barrier for the transdermal absorption of geniposide, and the transdermal absorption effect of the active ingredients is related to the particle size and the hydration of the skin. In order to enable geniposide to penetrate through the skin to reach an inflammation part more effectively, the inventor coats the geniposide by using sucrose-cocoate and isopropyl myristate to obtain a drug-loaded particle; compared with uncoated geniposide, the stability of the drug-loaded particles is improved; compared with the geniposide directly dispersed in water, the coated geniposide has the advantages that the release of the active ingredients is more uniform and stable, and the adverse effect caused by overhigh local concentration due to quick release of the medicine can be reduced.
The inventor carries out hydroformylation treatment on sodium alginate, and then performs nucleophilic addition reaction on carbonyl and silane containing amino to prepare a hybrid polymer solution, and the finally prepared kuh-seng total alkali transdermal absorption nano microemulsion has stronger binding capacity with platelets than a traditional sodium alginate base material; therefore, after the microemulsion is attached to the bleeding part of the wound, the formation of scabs is facilitated, the microemulsion is tightly attached to the wound, and the infection of external pollution components to the wound is further prevented.
The combination of glucomannan and the non-ionic surfactant in the solution of the hybrid polymer can form a thin film of surfactant at a higher concentration on the surface of the particles, providing sufficient viscosity and stability.
Preferably, the parameters of the ultrasonic treatment in step S1 and step S5 are each independently: the ultrasonic power is 550-800W, the ultrasonic frequency is 28-40 kHz, and the ultrasonic treatment is 15-45 min.
Preferably, the reaction temperature of the reaction in the step S2 is 38-42 ℃, and the reaction time is 3-9 h.
Preferably, the phosphate buffer solution prepared in step S3 is prepared by: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
Preferably, the reaction temperature of the hybridization reaction in the step S3 is 32-40 ℃, and the reaction time is 6-18 h.
Preferably, the concentration of the hydrochloric acid in the step S5 is 0.5-2 mol/L.
Preferably, the temperature of the cooling gelation in the step S5 is 0-4 ℃, and the time is 2-6 h.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The introduction and the function of part of raw materials in the formula of the invention are as follows:
geniposide: an iridoid glucoside is easily soluble in water, and is the main effective component of fructus Gardeniae; geniposide has obvious curative effect on diseases of digestive system, cardiovascular system and central nervous system, and has certain anti-inflammatory and soft tissue injury treating effects. The invention is used as herbal anti-inflammatory active ingredients.
The total matrine is a mixture of various alkaloids, is mainly extracted from traditional Chinese herbal medicines such as sophora flavescens, sophora alopecuroides, sophora subprostratae and the like, belongs to plants in Sophora and leguminous in the aspect of plant classification, has various pharmacological actions and efficacies, and is the main component of the Chinese herbal medicines for playing pharmacological actions and efficacies. The two main components with the highest content of matrine are matrine and oxymatrine.
1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride: a chemical agent that is a coupling agent for the hapten; it is easy to absorb moisture and soluble in ethanol and water.
N-hydroxysuccinimide: white to off-white crystals for the synthesis of amino acid protecting agents.
The invention has the beneficial effects that:
compared with the prior art, the geniposide is coated by sucrose-cocoate and isopropyl myristate to obtain drug-loaded particles; compared with uncoated geniposide, the stability of the drug-loaded particles is improved; compared with the geniposide directly dispersed in water, the coated geniposide has the advantages that the release of the active ingredients is more uniform and stable, and the adverse effect caused by overhigh local concentration due to quick release of the medicine can be reduced.
Compared with the prior art, the invention uses the hybrid polymer solution to be gelled with the emulsion coated with the anti-inflammatory component so as to prepare the matrine transdermal absorption nano microemulsion; the matrine transdermal absorption nano microemulsion has a three-dimensional network structure and good ductility, and meanwhile, the structure has the characteristic of porosity and can provide an enough passage for the release of anti-inflammatory components.
Compared with the prior art, the prepared total matrine transdermal absorption nano microemulsion has stronger binding capacity with platelets than the traditional sodium alginate base material; therefore, after the microemulsion is attached to the bleeding part of the wound, the formation of scabs is facilitated, the microemulsion gel is tightly attached to the wound, and the infection of external pollution components to the wound is further prevented.
Compared with the prior art, the total matrine transdermal absorption nano microemulsion prepared by the invention adopts the combination of glucomannan and the nonionic surfactant in the hybrid polymer solution to form a layer of film of the surfactant with higher concentration on the surface of the particles, and the carrier particles have stable quality in the long-term storage process, do not generate aggregation or disintegration, and improve the photo-thermal stability.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Some raw material parameters in the comparative examples and examples of the invention are as follows:
geniposide, CAS No.: 2452-63-8;
sucrose-cocoate, CAS number: 91031-88-8;
isopropyl myristate, CAS number: 110-27-0;
1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, CAS No.: 25952-53-8;
n-hydroxysuccinylidene, CAS No.: 6066-82-6.
Matrine, CAS number: 519-02-8.
Example 1
A transdermal absorption nano microemulsion is prepared by the following method:
s1, dissolving 3g of geniposide in 120g of water to obtain a geniposide water solution;
s2, dissolving 54g of sodium alginate in 300g of phosphate buffer solution, adding 2.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2g N-hydroxysuccinimide, and mixing to obtain a sodium alginate solution;
s3, mixing the geniposide aqueous solution and the sodium alginate solution, adjusting the pH of the solution to 5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion.
The preparation method of the phosphate buffer solution in the step S2 comprises the following steps: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
The concentration of the hydrochloric acid in the step S3 is 1 mol/L.
The parameters of the ultrasonic processing in step S3 are: the ultrasonic power is 550W, the ultrasonic frequency is 40kHz, and the ultrasonic treatment is carried out for 30 min.
The temperature of the cooling gelation in the step S3 is 4 ℃, and the time is 3 h.
Example 2
A transdermal absorption nano microemulsion is prepared by the following method:
s1 mixing 80g of sucrose-cocoate with 120g of isopropyl myristate to obtain an oil phase mixture; dissolving 3g of geniposide in 120g of water to obtain a geniposide water solution; mixing the oil phase mixture with a geniposide water solution, and performing ultrasonic treatment to obtain a geniposide emulsion;
s2, dissolving 54g of sodium alginate in 300g of phosphate buffer solution, adding 2.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2g N-hydroxysuccinimide, and mixing to obtain a sodium alginate solution;
s3, mixing the geniposide emulsion with the sodium alginate solution, adjusting the pH of the solution to 5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion.
The ultrasonic processing parameters in step S1 and step S3 are both: the ultrasonic power is 550W, the ultrasonic frequency is 40kHz, and the ultrasonic treatment is carried out for 30 min.
The preparation method of the phosphate buffer solution in the step S2 comprises the following steps: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
The concentration of the hydrochloric acid in the step S3 is 1 mol/L.
The temperature of the cooling gelation in the step S3 is 4 ℃, and the time is 3 h.
Example 3
A transdermal absorption nano microemulsion is prepared by the following method:
s1, dissolving 3g of geniposide in 120g of water to obtain a geniposide water solution;
s2, dissolving 3.5g of sodium periodate in 150g of water to obtain an aqueous solution of sodium periodate; adding 54g of sodium alginate and 15g of ethylene glycol into the sodium periodate aqueous solution, and reacting under a light-free condition; filtering the reaction product to obtain filtrate, and freeze-drying to obtain hydroformylation sodium alginate;
s3, dissolving the hydroformylation sodium alginate in 300g of phosphate buffer solution, and continuously adding 22g of gamma-aminopropyl triethoxysilane and 20g of tetraethoxysilane to perform hybridization reaction to obtain hybridization reaction solution;
s4, adding 2.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2g N-hydroxysuccinimide into the hybridization reaction solution, and mixing to obtain a hybridization polymer solution;
s5, mixing the geniposide aqueous solution and the hybrid polymer solution, adjusting the pH of the solution to 5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion.
The reaction temperature of the reaction in step S2 was 42 ℃ and the reaction time was 4.5 h.
The preparation method of the phosphate buffer solution in the step S3 comprises the following steps: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
The reaction temperature of the hybridization reaction in the step S3 is 32 ℃, and the reaction time is 9 h.
The concentration of the hydrochloric acid in the step S5 is 1 mol/L.
The parameters of the ultrasonic processing in step S5 are: the ultrasonic power is 550W, the ultrasonic frequency is 40kHz, and the ultrasonic treatment is carried out for 30 min.
The temperature of the cooling gelation in the step S5 is 4 ℃, and the time is 3 h.
Example 4
A transdermal absorption nano microemulsion is prepared by the following method:
s1 mixing 80g of sucrose-cocoate with 120g of isopropyl myristate to obtain an oil phase mixture; dissolving 3g of geniposide in 120g of water to obtain a geniposide water solution; mixing the oil phase mixture with a geniposide water solution, and performing ultrasonic treatment to obtain a geniposide emulsion;
s2, dissolving 3.5g of sodium periodate in 150g of water to obtain an aqueous solution of sodium periodate; adding 54g of sodium alginate and 15g of ethylene glycol into the sodium periodate aqueous solution, and reacting under a light-free condition; filtering the reaction product to obtain filtrate, and freeze-drying to obtain hydroformylation sodium alginate;
s3, dissolving the hydroformylation sodium alginate in 300g of phosphate buffer solution, and continuously adding 22g of gamma-aminopropyl triethoxysilane and 20g of tetraethoxysilane to perform hybridization reaction to obtain hybridization reaction solution;
s4, adding 2.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2g N-hydroxysuccinimide into the hybridization reaction solution, and mixing to obtain a hybridization polymer solution;
s5, mixing the geniposide emulsion with the hybrid polymer solution, adjusting the pH of the solution to 5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion.
The ultrasonic processing parameters in step S1 and step S5 are both: the ultrasonic power is 550W, the ultrasonic frequency is 40kHz, and the ultrasonic treatment is carried out for 30 min.
The reaction temperature of the reaction in step S2 was 42 ℃ and the reaction time was 4.5 h.
The preparation method of the phosphate buffer solution in the step S3 comprises the following steps: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
The reaction temperature of the hybridization reaction in the step S3 is 32 ℃, and the reaction time is 9 h.
The concentration of the hydrochloric acid in the step S5 is 1 mol/L.
The temperature of the cooling gelation in the step S5 is 4 ℃, and the time is 3 h.
Example 5
A matrine transdermal absorption nanometer microemulsion is prepared by the following method:
s1 mixing 80g of sucrose-cocoate with 120g of isopropyl myristate to obtain an oil phase mixture; dissolving 3g of geniposide in 120g of water to obtain a geniposide water solution; mixing the oil phase mixture with a geniposide water solution, and performing ultrasonic treatment to obtain a geniposide emulsion;
s2, dissolving 3.5g of sodium periodate in 150g of water to obtain an aqueous solution of sodium periodate; adding 54g of sodium alginate and 15g of ethylene glycol into the sodium periodate aqueous solution, and reacting under a light-free condition; filtering the reaction product to obtain filtrate, and freeze-drying to obtain hydroformylation sodium alginate;
s3, dissolving the hydroformylation sodium alginate in 300g of phosphate buffer solution, and continuously adding 22g of gamma-aminopropyl triethoxysilane and 20g of tetraethoxysilane to perform hybridization reaction to obtain hybridization reaction solution;
s4, adding 2.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2g N-hydroxysuccinimide into the hybridization reaction solution, and mixing to obtain a hybridization polymer solution;
s5 mixing the geniposide emulsion, 20g of total matrines, 30g of glucomannan and the hybrid polymer solution, adjusting the pH of the solution to 5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion of the total matrines.
The ultrasonic processing parameters in step S1 and step S5 are both: the ultrasonic power is 550W, the ultrasonic frequency is 40kHz, and the ultrasonic treatment is carried out for 30 min.
The reaction temperature of the reaction in step S2 was 42 ℃ and the reaction time was 4.5 h.
The preparation method of the phosphate buffer solution in the step S3 comprises the following steps: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
The reaction temperature of the hybridization reaction in the step S3 is 32 ℃, and the reaction time is 9 h.
The concentration of the hydrochloric acid in the step S5 is 1 mol/L.
The temperature of the cooling gelation in the step S5 is 4 ℃, and the time is 3 h.
Test example 1
The transdermal absorption nano microemulsion transdermal release test method adopts Franz diffusion cell method. The microemulsion gel prepared in each example is coated on a medical adhesive plaster to prepare a test sample, and the drug loading rate of geniposide in the test sample is 250 mu g/cm2. The test is carried out by adopting an RT800 automatic sampling transdermal diffusion system (provided by Shenzhen Ruizu instruments and equipment Co., Ltd.); each group is provided with 6 diffusion cells, the volume of each diffusion cell is 7.5mL, and 0.9% of normal saline is selected as receiving liquid; the transdermal test selects the abdominal skin of the sucking pig as the penetration skin, removes subcutaneous fat, is cleaned by sterile normal saline and then is placed in a diffusion cell, and the contact area of the penetration skin and the test sample is 3cm2(ii) a The transdermal test temperature was 37 ℃ and the total test time was 36 h. The test data are presented as the arithmetic mean of the samples. The results of the permeation test of the transdermal absorption nano microemulsion are shown in table 1.
TABLE 1
The higher the cumulative permeation amount of geniposide represents the better the transdermal absorption effect of the corresponding examples. As can be seen from the comparison between the above examples, example 4 has the best transdermal absorption effect; this may be due to the small particle size of the emulsion particles formed by coating geniposide with sucrose-cocoate and isopropyl myristate, and the closer fit of example 4 to the skin being tested, which may help release and penetration of geniposide. In addition, as can be seen from table 1, the increase in the cumulative permeation amount is more uniform in example 4 than in other examples, and the cumulative permeation amount increases linearly with time; the reason for the phenomenon is probably that the matrine transdermal absorption nano microemulsion prepared by cooling and gelling the geniposide emulsion and the hybrid polymer solution under the acidic condition has the characteristic of a porous structure, can provide a proper path for the release of the anti-inflammatory component, enables the release of the active component to be more uniform and stable, can reduce the adverse effect caused by overhigh local concentration due to the quick release of the medicine, and is beneficial to keeping the long-term effectiveness of the anti-inflammatory active component.
Test example 2
In order to test the patch release effect of the transdermal absorption nano microemulsion in the skin bending state, the cumulative permeation amount of geniposide was tested by the method as described in test example 1. The difference of the test is that the attachment of the transdermal absorption nano microemulsion and the permeable skin on the horizontal plane in the test example 1 is replaced by: the transdermal absorption nano microemulsion and the permeable skin are attached on a plane which is bent by 90 degrees from the center so as to simulate the bending state of the skin. The total attachment area, the test steps and the result processing of the test were kept consistent with those of test example 1, the final accumulated permeation quantity result in test example 1 was taken as the control group of each example, and the attachment release test result of the transdermal absorption nano microemulsion in the skin bending state is shown in table 2.
TABLE 2
As can be seen from the comparison of the above examples, the bending of the test-permeated skin affects the cumulative permeation amount of geniposide, and the test results of the examples are all observed to be reduced compared with the horizontal attachment; the decrease of example 4 was the lowest, and the fluctuation was substantially kept small as compared with the control group. The reason for the phenomenon is probably that after the sodium alginate is subjected to hydroformylation treatment, a nucleophilic addition reaction is carried out on carbonyl and silane containing amino to prepare a hybrid polymer solution, and then the hybrid polymer solution and geniposide emulsion are prepared into the transdermal absorption nano microemulsion, wherein the inside of the transdermal absorption nano microemulsion has a three-dimensional network structure, and the molecules are connected through covalent bonds, so that the mechanical property is enhanced, and the ductility of the transdermal absorption nano microemulsion is improved; can be tightly attached along with the change of the skin shape, and is beneficial to the release and absorption of geniposide.
Test example 3
The ability of the transdermal absorption nanomicroemulsion to bind to platelets is shown by the platelet in vitro adhesion test, which is carried out by referring to the specific method in "platelet adhesion test (glass bead column method) normality and clinical case observation" (second department of medical and military university report 1982, phase 4); ordinary glass beads were used as a control, and the test group coated the glass beads with the microemulsion gels prepared in each example, and the thickness of the coating layer was 0.05 mm. The platelet-rich plasma used in the test was supplied by Jiangsu Kejing Biotech, Inc., the diameter of the glass beads used in the test was 0.8mm, each group of tests was repeated 4 times, and the results were averaged. The results of the platelet in vitro adhesion test are shown in Table 3.
TABLE 3
| Sample combination | Platelet adhesion rate (%) |
| Control group | 25.8 |
| Practice ofExample 1 | 30.5 |
| Example 2 | 37.3 |
| Example 3 | 49.2 |
| Example 4 | 77.4 |
| Example 5 | 76.5 |
As can be seen from the comparison of the above examples, the binding ability of the microemulsion gel prepared in example 4 to platelets is superior to that of the other examples. The reason for this phenomenon is probably that after the hydroformylation of sodium alginate, the carbonyl group and the silane containing amino group undergo nucleophilic addition reaction to prepare the hybrid polymer, so that the physicochemical properties of the microemulsion gel are changed, and the hybrid polymer is helpful for the aggregation of blood platelets when acting on skin wounds, thereby being more beneficial to the formation of scabs, enabling the microemulsion gel to be tightly attached to wounds, and further preventing the wounds from being infected by external pollution components.
Test example 4
Stability test of transdermal absorption nano microemulsion
The experimental method refers to master's paper "preparation of idebenone nanostructured lipid carrier and transdermal absorption research, authors: the method is carried out by a specific method in Libei, chemical industry institute of Tianjin university, 2012); 20g of the sample of the example were placed in an incubator at 40 ℃ and stored under conditions of 75% humidity and 3000lx light for 180 days, and the change in particle size and zeta potential was measured initially and after 180 days of storage. The test was repeated 3 times and the results averaged. The test results are shown in Table 4.
TABLE 4
It can be seen from the comparison of the above examples that the stability of the transdermal nano microemulsion prepared in example 5 under the conditions of temperature and light is the best, probably because the fusion between lipid matrixes and between the lipid matrix and the active agent is very easy to occur under the condition of high temperature light, so that the transdermal nano microemulsion system is unstable, and the particles are easy to aggregate and separate out. The glucomannan is adopted for treatment, and can be combined with the nonionic surfactant in the hybrid polymer solution to form a film of the surfactant with higher concentration on the surface of the particles, so that the solid-liquid lipid mixture in solid and liquid state in the nano microemulsion is absorbed through skin, the exchange between the solid particles and an external water phase is very slow, the influence of high temperature and illumination is not easy to occur, the carrier particles have stable quality in the long-term storage process, aggregation or disintegration is not generated, and the photo-thermal stability is improved.
Claims (7)
1. The transdermal absorption nano microemulsion of the total matrine is characterized in that the preparation method of the transdermal absorption nano microemulsion of the total matrine comprises the following steps by weight:
s1, mixing 7.5-10 parts of sucrose-cocoate with 7.5-12.5 parts of isopropyl myristate to obtain an oil phase mixture; dissolving 0.16-0.36 part of geniposide in 12-18 parts of water to obtain a geniposide water solution; mixing the oil phase mixture with a geniposide water solution, and performing ultrasonic treatment to obtain a geniposide emulsion;
s2, dissolving 0.25-0.5 part of sodium periodate in 15-30 parts of water to obtain a sodium periodate aqueous solution; adding 4.8-9 parts of sodium alginate and 1.5-3 parts of ethylene glycol into the sodium periodate aqueous solution, and reacting under a light-free condition; filtering the reaction product to obtain filtrate, and freeze-drying to obtain hydroformylation sodium alginate;
s3, dissolving the hydroformylation sodium alginate in 30-50 parts of phosphate buffer solution, and continuously adding 2.2-3.3 parts of gamma-aminopropyltriethoxysilane and 2-3 parts of tetraethoxysilane for hybridization reaction to obtain a hybridization reaction solution;
s4, adding 0.12-0.3 part of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.08-0.15 part of N-hydroxysuccinimide into the hybridization reaction solution, and mixing to obtain a hybridization polymer solution;
s5, mixing the geniposide emulsion obtained in the step S1, 1-3 parts of total matrines, 2-5 parts of glucomannan and the hybrid polymer solution, adjusting the pH value of the solution to 5-5.8 by using hydrochloric acid, and performing ultrasonic treatment and cooling gelation to obtain the transdermal absorption nano microemulsion of the total matrines.
2. The matrine transdermal absorption nano microemulsion according to the claim 1, which is characterized in that: the parameters of the sonication in steps S1 and S5 are each independently: the ultrasonic power is 550-800W, the ultrasonic frequency is 28-40 kHz, and the ultrasonic treatment is 15-45 min.
3. The matrine transdermal absorption nano microemulsion according to the claim 1, which is characterized in that: the reaction temperature of the reaction in the step S2 is 38-42 ℃, and the reaction time is 3-9 h.
4. The matrine transdermal absorption nano microemulsion according to the claim 1, wherein the preparation method of the phosphate buffer solution in the step S3 is as follows: 250mL of potassium dihydrogen phosphate aqueous solution with the molar concentration of 0.2mol/L and 118mL of sodium hydroxide aqueous solution with the molar concentration of 0.2mol/L are mixed, diluted to 1000mL by water and shaken up to obtain the phosphate buffer solution with the pH value of 7.0.
5. The matrine transdermal absorption nano microemulsion according to the claim 1, which is characterized in that: the reaction temperature of the hybridization reaction in the step S3 is 32-40 ℃, and the reaction time is 6-18 h.
6. The matrine transdermal absorption nano microemulsion according to the claim 1, which is characterized in that: the concentration of the hydrochloric acid in the step S5 is 0.5-2 mol/L.
7. The matrine transdermal absorption nano microemulsion according to the claim 1, which is characterized in that: and in the step S5, the temperature of the cooling gelation is 0-4 ℃, and the time is 2-6 h.
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